GLUT1 and Cerebral Glucose Hypometabolism in Human Focal Cortical Dysplasia Is Associated with Hypermethylation of Key Glucose Regulatory Genes

Focal cortical dysplasia (FCD) is a significant etiological factor in drug-resistant epilepsy, linked with disturbances in neurovascular metabolism. Our study investigated regulation of glucose-transporter1 (GLUT1) and cerebral hypometabolism within FCD subtypes. Surgically excised human brain specimens underwent histopathological categorization. A subset of samples was assessed for DNA methylation changes of glucose metabolism-related genes. We evaluated GLUT1, vascular endothelial growth factor alpha (VEGFα), monocarboxylate-transporter (MCT2), and mammalian target of rapamycin (mTOR) expression, measured glucose-lactate concentrations, and established correlations with patients' demographic and clinical profiles. Furthermore, we investigated the impact of DNA methylation inhibitor decitabine and hypometabolic condition on the uptake of [³H]-2-deoxyglucose and ATPase in epileptic-brain endothelial cells (EPI-EC). We observed hypermethylation of GLUT1 and glucose metabolic genes in FCD brain/blood samples and could distinguish FCDIIa/b from mild malformations of cortical development (mMCD), with oligodendroglial hyperplasia (MOGHE) and non-lesional brains. Low GLUT1 and glucose-lactate ratios corresponded to elevated VEGFα and MCT2 in FCDIIa/b vs. non-lesional tissues, independent of age, gender, seizure-onset, or duration of epilepsy. Increased mTOR-signaling in FCDIIa/b tissues was evident. Decitabine stimulation increased GLUT1, decreased VEGFα expression, restored glucose uptake and ATPase activity in EPI-ECs, and reduced mTOR and MCT2 levels in human embryonic-kidney cells. We demonstrated: hypermethylation of glucose regulatory genes distinguish FCDIIa/b from mMCD, MOGHE and non-lesional types, glucose uptake reduction is due to GLUT1 suppression mediated possibly by a GLUT1-mTOR mechanism; and DNA methylation regulates cellular glucose uptake and metabolism. Together, these studies may lead to GLUT1-mediated biomarkers and identify early intervention strategies in FCD.